Cachexia, a potentially lethal syndrome afflicting mammals, frequently complicates the treatment of infection, inflammation and cancer. It is characterized by profound weight loss caused by wasting of body fat (adipose) and muscle (protein). Tracey et al., J. Exp. Med., Vol. 167, 1211-1227 (March 1988). Lawson et al., Ann. Rev. Nutr., 2:277-301 (1982). Anorexia, anemia, and weakness may also occur in cachexia. Tracey et al., supra. Cachexia may further be characterized by, inter alia, depression of glucose level (hypoglycemia) and elevation of triglyceride level (hypertriglyceridemia).
Cachexia may result from diverse causes such as age, cancer, and infections by parasites and by microorganisms such as bacteria, fungi, viruses and protozoa. Both acute and chronic infections or illnesses frequently cause cachexia. In fact, most chronic, fatal, nonneoplastic diseases terminate in cachexia (e.g. chronic disseminated infections, or prolonged insufficiency of heart, lungs, liver, kidneys, or the small intestines). Lawson et al., Ann. Rev. Nutr., 2:277-301 (1982). Moreover, the syndrome is not alleviated by adequate caloric uptake. Indeed, weight loss may continue in cachexia even while an adequate diet is consumed. Silva et al., J. General Microbiology, Vol. 134, 1629-1633 (1988).
Researchers have studied cachexia induced by microbial infections, and by parasitic infections such as trypanosomiasis and leishmaniasis. Sherry et al., J. Cell Biology, Vol. 107, 1269-1277 (October 1988). The study of cachexia induced by microbial infections has shown that the syndrome may result from either the direct effect of the microorganism or from a toxin produced by the microorganism. For example, weight loss has been observed as a toxic manifestation in mice upon injection with endotoxin, the lipopolysaccharide (LPS) derived from gram-negative bacteria. Vogel et al., Infection and Immunity, Vol. 56, No. 10, 2650-2657 (October 1988).
Indeed, the toxin produced by a microorganism has been used to create a model for the study of cachexia. In this regard, cachexia has been induced by intraperitoneal injection into mice of trehalose dimycolate (TDM) isolated from Nocardia asteroides. Silva et al., J. General Microbiology, Vol. 134, 1629-1633 (1988). Researchers have studied the mechanism by which TDM, also known as cord factor (CF), a toxic glycolipid from mycobacteria, induces cachexia. Silva et al., Infection and Immunity, Vol. 56, No. 12, 3067-3071 (December 1988). That laboratory observed that administration of CF markedly reduced body weight: the animals became severely wasted and exhibited hypertriglyceridemia, hypoglycemia, and high levels of tumor necrosis factor in plasma. Dexamethasone was found to partially inhibit the cachexia-inducing action of CF.
Recent research has focused on the physiology related to cachexia. For example, the increase in circulating triglycerides observed has been attributed to systemic suppression of lipoprotein lipase (LPL). Tracey et al., J. Exp. Med., Vol. 167, 1211-1227 (March 1988). It has been reported, however, that transplantable adenocarcenoma of the colon (MAC16) produces cachexia symptoms without concomitant hypertriglyceridemia. Mahony et al., Br. J. Cancer, 57, 385-389 (1988) .
It has also been suggested that tumor necrosis factor, hereinafter "TNF" also known as "cachectin", Beutler et al, Advances in Immunology, Vol. 42, 213-231 (1988), may play a central role in cachexia. Tracey et al., J. Exp. Med., Vol. 167, 1211-1227 (March 1988). Michie et al., Surgery, Vol. 104, No. 2, 280-286 (August 1988), reports that TNF may represent the primary stimulus that initiates many of the metabolic responses associated with sepsis and endotoxemia.
The role of TNF, however, is not clear. Although cachexia in cancer patients has been associated with the presence of TNF, this factor has not been uniformly detectable in the serum of cachectic patients with cancer. Sherry et al., The FASEB J., Vol. 3, 1956-1962 (June, 1989). In one study, using both cachexia-inducing (MAC16) and non-cachexia-inducing (MAC13) adenocarcinomas, researchers concluded that weight loss produced by TNF arises from an anorexic effect that differs from the complex metabolic changes associated with cancer cachexia. Mahony et al., Br. J. Cancer, 57, 385-389 (1988). Similarly, in a study on viral-related cachexia, using mice infected persistently with lymphocytic choriomeningitis virus (LCMV), the laboratory concluded that the greater than 20% cachexia-like weight loss observed was apparently not associated with a measurable increase in TNF. Lathey et al., Am. J. Pathol., 132(3):586-92 (September 1988).
The severe weight loss and debilative wasting of lean body mass of cachexia frequently complicates the treatment of patients suffering from malignancy or chronic infection. Indeed, cachexia contributes to cancer mortality. Some data indicate that as many as 30% of cancer patients die from cachexia, rather than tumor burden. Tracey et al., supra. One medical textbook notes that:
"[t]he most common way in which malignancy leads to death is cachexia: the development of progressive weakness, weight loss, and wasting. Usually, there is a close correlation between the amount of malignant disease present and the severity of cachexia... In this weakened state, cancer patients are particularly susceptible to terminal infections, such as pneumonia, which often precipitates death." van Eys, Ann. Rev. Nutr., 5:435-61 (1985) (based on the second edition of Robbins' Textbook of Pathology).
The severity of cachexia may be unrelated to tumor size or parasite load, and profound wasting has been observed in patients with tumor burdens of only 0.01 to 5.0% body mass. If not reversed, physiological changes associated with cachexia lead to immunological deficiencies, organ failure, and multiple metabolic abnormalities. Tracey et al., J. Exp. Med., 167, 1211-1227 (March 1988). Theologides, Cancer, May Supplement, 43, 2004-2012 (1979).
The physiological changes due to cachexia decrease the patient's tolerance to chemotherapy and radiation therapy, as well as increase the frequency of post-surgical complications. The nausea, vomiting, and anorexia induced by chemotherapeutic agents as well as radiation injury can be very severe. In addition, chemotherapy is a major factor in malnutrition. It is well recognized that therapy is often as debilitating as the cancer itself. The malnourished patient has a much narrower safe therapeutic margin for most oncologic therapy. van Eys, Supra.
Further, median survival has been found to be significantly shorter in patients who had lost weight with most types of tumor examined. Lawson et al., Ann. Rev. Nutr., 2:277-301 (1982).
The precise mechanisms by which the cachexia syndrome may cause death in some patients and perhaps contribute to it in others are not completely understood. Lawson et al., Ann. Rev. Nutr., 2:277-301 (1982). Thus, the art has continued to search for effective methods for treating cachexia resulting from etiologies such as cancer or infectious diseases.